Despite the fact that there are multiple etiologies of Alzheimer's disease (AD), all AD cases share the neuropathological hallmark of amyloid-Beta peptide (Abeta) plaques and neurofibrillary tangles in brain, indicating a possible common pathway of AD pathogenesis. Apolipoprotein E4 (ApoE4) has been identified as a major risk factor of late-onset AD, but approximately 50% of cases do not carry the ApoE4 allele. Interestingly, hyperinsulinaemia is found to be associated with AD cases in the absence of ApoE 4 influence. 37% of AD subjects suffer from impaired glucose tolerance, presumably also having elevated plasma insulin, compared to 19.9% of non-AD subjects in the same population. The major hypothesis of the proposed study is that hyperinsulinaemia is another risk factor of late-onset AD in the absence of ApoE4. Insulin and AB, the major component in AD pathology, share biochemical features. Both are short peptides with amyloidogenic properties, and both are degraded by a common protease, insulin-degrading enzyme (IDE). To explore the mechanism of how hyperinsulinaemia might contribute to AD, our secondary hypothesis is that in hyperinsulinaemia insulin competes with AB for IDE, increasing the amount AB and thus causing AD pathology. To translate the candidate's basic research on IDE and ABeta into clinical research on AD, this proposal presents a multi-faceted and collaborative study. By collaborating in a project that will recruit 1600 homebound elderly in Boston, subjects will be available to evaluate the relationship between insulin levels with cognitive impairment and AD. Subjects who do not carry ApoE4 and have not received insulin treatment will meet study criteria. Quantitative correlation will be evaluated between fasting plasma insulin level and cognitive impairment in the absence of ApoE4. Clinical examination and MRI scans will be performed on a subset of 473 subjects to evaluate the association of hyperinsulinaemia in AD vs. non-AD subjects. Hyperinsulinaemia is present in some but not all cases of type 2 diabetes. Because hyperinsulinaemia rather than type 2 diabetes alone may be the relevant risk factor of AD, the association of AD with hyperinsulinaemia vs. type 2 diabetes will also be analyzed. We will determine whether levels of insulin and cognitive function are correlated with Aa levels and IDE activity. Results from this study should provide a rationale to determine if elevated insulin increases the incidence of AD in a prospective study.